Natalie Otto

Hyperosmotic stress enhances cytokine production and decreases phagocytosis in vitro

IntroductionHyperglycemia is associated with negative outcomes in various settings of critical illness; infectious complications, especially, seem to be increased. On the other hand, intensive insulin therapy (IIT) has been shown to improve outcome in clinical trials. Whether normoglycemia itself or the application of insulin is responsible for the observed findings is unknown. We therefore tested the effect of glucose and insulin on various immune functions in vitro.MethodsHuman peripheral blood mononuclear cells (PBMCs) were incubated ex vivo with low doses of lipopolysaccharide (LPS). PBMCs were incubated with various osmotic agents, insulin, or a combination of both. Interleukin (IL)-6 and IL-1 cytokine response was measured by enzyme-linked immunosorbent assay. In addition, we investigated the effects of glucose on phagocytosis and oxidative burst in human granulocytes.ResultsIncreasing concentrations of both glucose and mannitol significantly enhanced LPS-induced cytokine production. Insulin alone did not alter cytokine production and had only a minor influence in combination with glucose. Phagocytosis and oxidative burst were significantly reduced with increasing concentrations of glucose and mannitol.ConclusionHyperglycemia may lead to inflammation by enhancing cytokine production via the direct effects of hyperosmotic stress. Impaired phagocytosis and oxidative burst under hyperglycemia may weaken defense mechanisms of the host. Our in vitro findings may help to explain the beneficial effects of IIT not only in diabetic but also in critically ill patients.

Simultaneous pancreas/kidney transplant recipients are predisposed to tissue-invasive cytomegalovirus disease and concomitant infectious complications

Infections have increased in simultaneous pancreas/kidney transplant recipients (SPKTRs) with cytomegalovirus (CMV) infection being the most important viral infection with adverse impact on patient and allograft outcomes.

Methods to safely implement hypothermia in the intensive care unit: a how-to guide

Target temperature management (TTM) is well-known to reduce secondary cell damage after cardiac arrest in patients with presumed cerebral hypoxia. The treatment of this reperfusion syndrome, especially in terms of temperature management, is not fully understood. Several clinical randomized controlled trials and other studies have shown TTM’s effectiveness in improving neurological outcomes.(1) Therefore, TTM has been recommended in the updated guidelines of the European Resuscitation Council since October 2015.(2) Briefly, TTM is indicated for almost all survivors after cardiac arrest with different levels of evidence supporting this claim. The initial rhythm (shockable or non-shockable) and the location of the arrest (in-/out-of-hospital cardiac arrest) do not exclude treatment if the patient remains comatose after the return of spontaneous circulation. Due to new published data, the recommended target temperature is between 32°C and 36°C for 24 hours; the optimal target temperature and duration of cooling is still unknown.(3) In addition, modern TTM is only a part of the care for the post-cardiac arrest phase, including early percutaneous coronary intervention, optimization of blood glucose levels and ventilator setup to achieve normoxia and normocapnia. Several surveys in Europe revealed an increasing acceptance of TTM after cardiac arrest, but there is still an intermediate rate of using professional computer feedback guided temperature management and the standard operating protocol (SOP).(4-6) The reasons behind the reluctance are numerous. When comparing the benefit of using TTM with neurological outcomes and recovery, some of these reasons will no longer acceptable in the future.

Criteria and Relevant Prognostic Factors in Donor Selection, an Analysis of 266 Consecutive Donor Nephrectomies.

Objectives The proportion of kidney transplants from live donors has steadily increased in recent years. In comparison to postmortem donation, living donor kidney transplantation results in shortening of the waiting period, significantly better transplant survival and less post-operative complications. In particular, choosing donors requires a comprehensive pre-operative evaluation for a careful selection. Aim of our analysis was to investigate relevant prognostic parameters and selection criteria in healthy kidney donors with respect to donor and recipient outcomes. Methods A retrospective analysis of a total of 266 consecutive renal transplantation was carried out for the period from January 2010 till September 2017, including radiological imaging, renal clearance, operation time as well as intra- and postoperative outcomes. Further, subgroup analysis for donors with anatomical vascular variations was done. Results Kidney donors were on average 53.3 years old [95% confidence interval (CI) 51.97 – 54.60, Standard deviation (SD) 10.71], the gender ratio (male: female) was 41% to 59%. 96% of renal donor donations were performed in a laparoscopic approach, 4% in open-surgical technique. Nephrectomy was carried out on the right side in 45% and on the left side in 55% of the donors. Mean creatinine clearance of the corresponding kidney was 49.6%. Anatomical vascular variations (>1 renal artery or vein) were present in 26% of the donors. The mean operative time was 208.7 minutes (CI 202.84 – 213.49, SD 42.69). Mean operative time for the multiple arteries (CI 204.24 – 223.14, SD 42.85) showed no relevant statistical differences [p-Value (PV) 0.18] compared to kidney with a single artery. Postoperative complications > Dindo-Clavien II occurred in less than 2% of the donors. Conclusions Nowadays, a live donor nephrectomy can be safely carried out. However, preoperative donor evaluation and selection requires a careful assessment, taking into account a personalised approach for all individual donor-specific risk factors.

Two Decades of Eurotransplant Senior Program (ESP): Time on Dialysis Independently Impacts Patient Survival, Allograft Survival and Quality of Life After Kidney Transplantation

Background In 1999, the Eurotransplant Senior Program (ESP) was implemented within the Eurotransplant kidney allocation scheme, due to an increasing number of older recipients and donors. The ESP allocates kidneys from deceased-donors ≥65 years to kidney transplant recipients ≥65 years (ESP-KTRs), and aims to shorten cold ischemic time by leaving out HLA matching and regional allocation. Methods We analyzed patient and kidney allograft outcomes of 244 ESP-KTRs between 1999 and 2017. All ESP-KTRs were assessed by a questionnaire-based survey with respect to mental and physical health using the standardized short form-8 questionnaire (SF-8). A control group of 82 dialysis patients waitlisted within the ESP was used for comparison. Results We observed 1-year, 5-year, and 10-year patient survival of 92.5%, 67.6%, and 38.2%, respectively. Upon multivariate analysis mortality risk factors included prolonged initial hospital stay (p=0.004), male gender (p=0.017), and time on dialysis (p=0.012). 1-year, 5-year, and 10-year death-censored allograft survival was 92.1%, 81.0%, and 70.0%, respectively. Risk factors that were independently associated with allograft loss included time on dialysis (p<0.001) and acute cellular rejection (p<0.001). After re-initiation of dialysis treatment after allograft loss median patient survival was 46 months (range: 0-152 months). No ESP-KTR underwent retransplantation after allograft loss. We observed 1-year, 5-year, and 10-year uncensored allograft survival of 85.2%, 55.4%, and 26.7%, respectively. 45.1 % of ESP-KTRs showed delayed graft function and 3.7% of ESP-KTRs showed primary non-function. Kidney allograft function at 1-year, 5-years, and 10-years posttransplantation were 44.6mL/min, 40.5mL/min, and 39.1mL/min, respectively. Median physical and mental component scores (PCS/MCS) of ESP-KTRs were 40.2 (range: 16.9-62.5) and 48.3 (range: 21.1-62.5), respectively, and significantly higher compared to dialysis patients waitlisted within the ESP (p<0.05). The only factors, that were independently associated with inferior PCS and MCS after kidney transplantation, were recipient age (p=0.013) and time on dialysis (p=0.043). 97% of ESP-KTRs who underwent successful kidney transplantation would choose again to do so. Conclusion Kidney transplantation within the ESP shows highly favorable patient and allograft outcomes independent of recipient and donor age. However, prolonged time on dialysis significantly impacts patient and allograft outcomes and accounts also for inferior quality of life after successful kidney transplantation. This finding may be attributed to longer time from medical evaluation to transplantation among those ESP-KTRs and call for more frequent and critical medical re-evaluation.

Factors and outcomes in association with sepsis differ between simultaneous pancreas/kidney and single kidney transplant recipients

As immunosuppressive therapy has improved in simultaneous pancreas/kidney transplant recipients (SPKTRs), infection has become the major limitation of disease‐free survival.

Transplantectomy is associated with presensitization with donor-reactive T cells and graft failure after kidney retransplantation: a cohort study

Background The number of kidney transplant recipients (KTRs) being waitlisted for a subsequent transplantation has disproportionately increased to almost 25%. Evidence for the optimal management of the failed allograft, however, remains inconsistent. Methods We studied 111 KTRs who underwent their second kidney transplantation from 1998 to 2015. In 51/111 KTRs (46%) the failed allograft was removed and in 60/111 (54%) the failed allograft was retained. KTRs with primary non-function and allograft loss <12  months of the first failed allograft were excluded from analysis. Samples were collected before transplantation and at  1  month posttransplantation and donor-reactive T cells were measured using an interferon-γ enzyme-linked immunosorbent spot assay. Results KTRs with the previous allograft removed showed significantly higher rates of acute cellular rejection compared with KTRs with the previous allograft retained [27/51 KTRs (53%) versus 18/60 KTRs (30%); P = 0.019]. KTRs with the previous allograft removed showed significantly inferior death-censored allograft survival compared with KTRs with the previous allograft retained (P = 0.022). Here, KTRs with the previous allograft removed showed significantly higher donor-reactive T cells pretransplantation compared with KTRs with the previous allograft retained (P = 0.012). Interestingly, no differences were observed for the presence of panel reactive antibodies and for the development of de novo donor-specific antibodies. Conclusions Our data suggest higher cellular presensitization among KTRs with the previous allograft removed, which is associated with higher rates of acute cellular rejection and inferior allograft survival. Immunological mechanisms that may account for these differences may include prolonged maintenance immunosuppression to save urine output in KTRs with the first kidney allograft retained and cellular presensitization after withdrawal of maintenance immunosuppression, which lead to allograft rejection and ultimately to allograft nephrectomy.

Cyclosporine use and male gender are independent determinants of avascular necrosis after kidney transplantation: a cohort study

Background Kidney transplant recipients (KTRs) are at increased risk of avascular necrosis (AVN) due to bone disorder, steroid use and common comorbidities. However, knowledge on risk factors and outcomes of AVN among KTRs in the modern era of immunosuppression remains scarce. Methods We analysed 765 KTRs between 2001 and 2013 for AVN. Cases of symptomatic AVN were diagnosed by hip X-ray, radioisotope bone scan or magnetic resonance imaging. We evaluated risk factors and clinical characteristics of AVN. Results KTRs showed a constant incidence rate of AVN of 4.1% at 10 years after transplantation. The use of cyclosporine compared with tacrolimus was identified as an independent risk factor, with a rate of 8.0% compared with 2.7% at 10 years (P < 0.01). In addition, male gender was independently associated with AVN (P = 0.047). Eighty-three per cent of AVN cases were of the femoral head and treated operatively. None of the operated KTRs experienced complications in the long term. Thirty-three per cent of KTRs had bilateral AVN. Ninety-two per cent of KTRs showed AVN at the allograft side. Conclusions The decreasing incidence of AVN may be attributed to the replacement of cyclosporine by tacrolimus over the last decade. Our data raise the hypothesis of an ischaemic steal syndrome due to the allograft kidney impacting AVN at the allograft side.

Impact of acute kidney injury on neurological outcome and long-term survival after cardiac arrest – A 10 year observational follow up

Background: Acute kidney injury (AKI) may be associated with short‐ and long‐term patient morbidity and mortality. Therefore, the impact of AKI after cardiac arrest on survival and neurological outcome was evaluated. Methods: An observational single center study was conducted and consecutively included all out and in hospital cardiac arrest (OHCA/IHCA) patients treated with therapeutic temperature management between 2006 and 2013. Patient morbidity, mortality and neurological outcome according to the widely used Pittsburgh Cerebral Performance Category (CPC) were assessed. A good neurological outcome was defined as a CPC of 1–2 versus a poor neurological outcome with a CPC of 3–5. AKI was defined by using the KDIGO Guidelines 2012. Results: 503 patients were observed in total. 29.4% (n = 148) developed AKI during their intensive care unit (ICU) stay. 70.6% (n = 355) did not experience AKI. The mean age at admission was 62 years, of those 72.8% were male and 77% experienced an out‐of‐hospital cardiac arrest (OHCA). AKI occurred with 41.2% more often in the group with poor neurological outcome compared to 17.1% in the group with good neurological outcome. The median survival for patients after cardiac arrest with AKI was 0.07 years compared to 6.5 years for patients without AKI. Conclusion: Our data suggest that AKI is a major risk factor for a poor neurological outcome and a higher mortality after cardiac arrest. Further important risk factors were age, time to ROSC and high NSE. HighlightsAKI is a major risk factor for a poor neurological outcome after cardiac arrest.AKI predisposes to a higher mortality among those who survived cardiac arrest.AKI may reflect both, more severe chronic comorbid conditions and the extent of cardiac disease.